A drug screening pipeline using 2d and 3d patient-derived in vitro models for pre-clinical analysis of therapy response in glioblastoma

Sakthi Lenin, Elise Ponthier, Kaitlin G. Scheer, Erica C.F. Yeo, Melinda N. Tea, Lisa M. Ebert, Mariana Oksdath Mansilla, Santosh Poonnoose, Ulrich Baumgartner, Bryan W. Day, Rebecca J. Ormsby, Stuart M. Pitson, Guillermo A. Gomez

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Glioblastoma is one of the most common and lethal types of primary brain tumor. Despite aggressive treatment with chemotherapy and radiotherapy, tumor recurrence within 6–9 months is common. To overcome this, more effective therapies targeting cancer cell stemness, invasion, metabolism, cell death resistance and the interactions of tumor cells with their surrounding microen-vironment are required. In this study, we performed a systematic review of the molecular mechanisms that drive glioblastoma progression, which led to the identification of 65 drugs/inhibitors that we screened for their efficacy to kill patient-derived glioma stem cells in two dimensional (2D) cul-tures and patient-derived three dimensional (3D) glioblastoma explant organoids (GBOs). From the screening, we found a group of drugs that presented different selectivity on different patient-derived in vitro models. Moreover, we found that Costunolide, a TERT inhibitor, was effective in reducing the cell viability in vitro of both primary tumor models as well as tumor models pre-treated with chemotherapy and radiotherapy. These results present a novel workflow for screening a relatively large groups of drugs, whose results could lead to the identification of more personalized and effective treatment for recurrent glioblastoma.

Original languageEnglish
Article number4322
Number of pages27
JournalInternational Journal of Molecular Sciences
Volume22
Issue number9
DOIs
Publication statusPublished - 21 Apr 2021

Keywords

  • Drug screening
  • Glioblastoma
  • Organoids
  • Personalized medicine
  • Therapy resistance
  • Tumor microenvironment

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